Motilin is a gastrointestinal linear polypeptide hormone which stimulates the gastric antrum, duodenum, and colon. Although its effects are not completely known, motilin plays a role in increasing gastric motility and stimulating pepsin output and may also be important in regulating the interdigestive myoelectric complex. Human motilin has not yet been purified, but its immunologic properties strongly suggest that it is very similar to porcine motilin. Porcine motilin contains amino acid residues and may be represented by the formula: ##STR2##
Porcine motilin has a hydrophobic region from positions 1 to 5, a hydrophilic region from positions 11 to 22, and a connecting region from positions 6 to 10. Porcine motilin also has an .alpha.-helical secondary structure from residues 9 to 20 of the primary sequence [Khan et al., Biochemistry 29, 5743-5751 (1990)].
Administration of motilin to healthy human subjects accelerates intestinal transit time and enhances gastric emptying. In vitro, motilin stimulates contractions of human and rabbit duodenal smooth muscle strips and isolated gastrointestinal smooth muscle cells. In addition, motilin and some of its derivatives compete with radiolabelled motilin for binding sites on human and rabbit antral tissue suggesting that stimulation of specific receptors in the gastrointestinal tract is responsible for the physiological effects of the hormone. Infusion of motilin has been reported to stimulate the emptying of solids and liquids in patients with diabetic gastroparesis [Peeters et al., Gastroenterology 100, A480 (1991)]. In addition, motilin has been used to treat patients with paralytic ileus caused by carcinoma of the gastrointestinal tract [Meyer et al., Med. Klin. 86, 515-517 (1991)]. Motilin has a relatively short half-life (t.sub.1/2) of 4.5 minutes in humans, Christofides et al., Gastroenterology 76, 903-907(1979), which makes it necessary to administer the hormone by continuous infusion to induce a therapeutic effect.
The N-terminal amino acid sequence and certain residues of the mid-portion of motilin are essential for contractile activity, [Macielag et al., Peptides 13, 565-569 (1992); Peeters et al., Peptides 13, 1103-1107 (1992); Poitras et al., Biochem. Biophys. Res. Commun. 183, 36-40 (1992)]. Motilin-like polypeptides which have a shorter C-terminus, contain from 3 to 5 basic amino acids bonded from position 12, and have various amino acid substitutions at positions 1 through 11 have been reported to have activity less than, or equal to, that of motilin.
A motilin antagonist which displaces labeled porcine motilin in rabbit smooth muscle has been reported, "The Motilin Antagonist ANQ-11125 Blocks Erythromycin-induced Contractions In Vitro", Peeters, T. L., Depoortere, I., Macielag, M. J., Dharanipragada, R., Marvin, M. S., Florance, J. R., Vantrappen, G., Galdes, A., Gastroenterology 1993, 104, A564.
Although a clear correlation has not been established between hypermotilinemia and disease, elevated plasma motilin levels have been observed in clinical conditions associated with gastrointestinal hypermotility syndromes such as infectious diarrhea and Crohn's disease. This observation suggests that an agent which inhibits the interaction of motilin with its receptor would be useful in the treatment of the disordered intestinal peristalsis associated with these conditions.
In addition, a motilin-like polypeptide having potent gastrointestinal motor inhibitory activity would be useful for the treatment of increased basal levels of gastrointestinal motor activity.